The ultimate goal of this project, development of an anti-TNF-1 drug for rheumatoid arthritis and/or other TNF-1 induced inflammatory diseases, remains unchanged from the original application. The Phase II project will build on the Phase I identification of a locked nucleic acid, splice switching oligonucleotide (LNA SSO) that effectively shifts splicing of the tumor necrosis factor receptor 2 (TNFR2) in vivo. As a result, TNFR2 targeted LNA SSOs upregulate an endogenous, soluble, circulating protein (7TNFR2) that serves as a TNF-1 antagonist in vivo. In Phase I, we established that systemically delivered LNA SSOs are highly effective at inducing significant concentrations of 7TNFR2 in the circulation of mice, and that this treatment yielded high and persistent anti-TNF-1 activity in vivo. We also established that LNA SSO treatment was effective in two mouse models of inflammatory disease: collagen induced arthritis and TNF-1 induced hepatitis. The objective of Phase II is to assess the efficacy and establish the safety profile of LNA SSOs in non-human primates, and also assess the potency of modified 2'MOE oligonucleotides, for use in our TNFR2 program. The experiments outlined in this proposal will lead to the identification of a lead LNA SSO compound for clinical trials, and a complementary SSO chemistry strategy. PUBLIC HEALTH RELEVANCE: Successful completion of the research proposed in this application will lead to development of novel drugs for rheumatoid arthritis and other inflammatory diseases. These drugs will reduce the inflammatory effects of TNF-alpha and in that they will be similar to an existing drug Enbrel. However, we anticipate that Ercole drugs, because of their novel design and mechanism of action, will be more effective, longer lasting and less costly than Enbrel and may benefit patients who never see significant improvement with current treatments.